The polypeptide of the present invention is a member of the natural killer cell activating factor (NKAF) family and shows homology to NKAF and human eosinophil major basic protein. Natural killer cells (NK cells) show a destructive effect on specific cancer cells. Lymphokines affecting the activity of these NK cells have therefore attracted attention. It is reported that interleukin-2 and interferon enhance the activity of NK cells (Herberman, R. B., et al., Immunol. Rev., 44:13 (1979); Vose, B. M., et al., J. Immunol., 130:768 (1983) and Domzig, W. et al., J. Immunol., 130:1970 (1983)).
NK cells are proposed to function as natural surveillance to deter cancer development in the body (Whiteside, T. and Herberman, R. B., Clin. Immunol. Immunopathol., 58:1–23 (1989) and Trinchieri, G., Adv. Immunol., 47:187–376 (1989)). NK cells are also important in controlling viral infection and the regulation of hematopoiesis (Trichieri, G., Adv. Immunol., 47:187–376 (1989); Kiessling, R., et al., Eur. J. Immunol., 7:655–663 (1977)).
The following facts indicate that NK cells play important roles in the host defense against cancer. Namely, a nude mouse lacking T cells by having a high NK activity does not always suffer from spontaneous or chemically induced carcinogenesis at a high frequency (Rygaard, J. et al., Immunol. Rev., 28:43 (1975); Stutman, D., et al., Science, 183:534 (1974)); and the metastasis of transplanted cancer cells is promoted in a beige mouse having T cells but a genetically low NK activity (Shimamura, K. and Tamaoki, K., Jikken Igaku, 2:398 (1984); James E. Talmadge, et al., Nature, 284:622 (1980)) and a mouse having an artificially lowered NK activity (Shimamura, supra).
Human eosinophil major basic protein (MBP) has a nearly identical sequence to that of known natural killer cell activating factor I. Human MBP is one of the principal mediators of injury to parasites in tissues in allergic inflammation. MBP is stored in eosinophil crystalloid granules and released with other granule constituents during eosinophil activation. MBP has no recognized enzymatic activity but it is toxic for some helminths (Ackerman, S. J. et al., Am. J. Trop. Med. Hyg., 34:735–745 (1985)) and mammalian cells (Barker, R. L. et al., J. Clin. Invest., 88:798–805 (1991)) in vitro. MBP is expressed principally in bone-marrow eosinophils, but it is also synthesized in basophils and placental trophoblast x-cells (Wasmoen, T. L. et al., J. Exp. Med., 170:2051–2063 (1989)).
MBP stimulates the effector function of a wide variety of cells, namely MBP stimulates the noncytolytic release of histamine from human basophils and rat mass cells (O'Donnell, M. A. et al., J. Exp. Med., 157:1981 (1983)). MBP also stimulates neutrophils to release superoxide and ion and lysozyme, but not beta-glucuronidase or lactic dehydrogenase, and MBP enhances the expression of CR3 and P150, 95 by neutrophils. This indicates that MBP activates other cells associated with inflammation, such as basophils, platelets and neutrophils. The effector mechanisms may play a role in pathophysiology of various diseases where granule proteins are released. For example, MBP has been thought a cause for increased airway responsiveness, for example, bronchial asthma.
The effects of the natural killer cell activating factors are varied and influence numerous functions, both normal and abnormal, in the biological processes of the mammalian system. There is a clear need, therefore, for identification and characterization of proteins that influence biological activity, both normally and in diseased states. In particular, there is a need to isolate and characterize additional natural killer cell activating factors akin to known natural killer cell activating factors which may be employed, therefore, for preventing, ameliorating or correcting dysfunctions or disease or augmenting positive natural actions of such receptors.